The American Society of Clinical Oncology (ASCO) 2024 conference was a remarkable event, bringing together leading minds in oncology to discuss the latest breakthroughs and research in cancer treatment. This year’s conference was particularly notable for the innovative approaches presented in the treatment of metastatic melanoma, a challenging and aggressive form of skin cancer. In this series, I will provide updates on some of the most compelling findings from the conference, starting with two groundbreaking abstracts that could significantly impact frontline treatment strategies in Metastatic Melanoma.
Triplet Checkpoint Therapy: A New Hope in Advanced Melanoma
In the realm of advanced melanoma, immune checkpoint inhibitors have revolutionized treatment, offering hope where there was little before. Nivolumab (NIVO), an anti–PD-1 antibody, is already approved as monotherapy and in combination with either relatlimab (RELA), an anti–LAG-3 antibody, or ipilimumab (IPI), an anti–CTLA-4 antibody. The RELATIVITY-048 study (NCT03459222) explored the efficacy and safety of a triplet combination therapy—NIVO, RELA, and IPI—in patients with advanced melanoma, marking the first disclosure from this significant trial.
Patients with advanced melanoma were enrolled and treated with a regimen consisting of NIVO 480 mg every four weeks, RELA 160 mg every four weeks, and IPI 1 mg/kg every eight weeks. The treatment continued until disease progression or the emergence of unacceptable toxicity. The primary endpoints of the study were safety and confirmed objective response rate (ORR), disease control rate (DCR), and median duration of response (DOR).
A total of 46 patients were treated in this study, with a median follow-up of 44.1 months. The patient cohort had a median age of 61 years, with a diverse representation including 8.7% with cutaneous acral melanoma and 50% with BRAF-positive tumors. Notably, 73.9% of patients were LAG-3 positive, and 26.1% were PD-L1 positive.
The combination therapy demonstrated a confirmed ORR of 58.7% and a remarkable 48-month OS rate of 69.1%. The safety profile was generally consistent with known immune-oncology combinations, with treatment-related adverse events (TRAEs) occurring in 95.7% of patients, and grade 3/4 TRAEs in 39.1%. Treatment discontinuation due to TRAEs occurred in 41.3% of patients, with two treatment-related deaths reported.
The findings from the RELATIVITY-048 trial are promising, indicating that the combination of NIVO, RELA, and IPI offers encouraging efficacy with a manageable safety profile. With a confirmed ORR of 58.7% and an impressive 48-month OS rate of 69.1%, this triplet therapy could represent a significant advancement in the frontline treatment of advanced melanoma. However, given the relatively small sample size, larger randomized studies are warranted to confirm these results and refine the treatment protocol.
Tumor-Infiltrating Lymphocytes (TIL) in Combination with Pembrolizumab
Despite significant advancements in the treatment of advanced melanoma, many patients do not achieve long-term benefits with current frontline therapies. Tumor-infiltrating lymphocyte (TIL) therapy represents a novel approach that has shown potential in inducing durable responses. This study evaluates the efficacy and safety of combining TIL therapy with pembrolizumab (pembro), an anti-PD-1 therapy, in patients with ICI-naive unresectable or metastatic melanoma. The NCI demonstrated a ORR of 55%, Complete Response of 25%, and 10 year Melanoma Specific Survival of 96% for these patients who had a complete response. And these were patients who never had prior checkpoint inhibitors.
The IOV-COM-202 (NCT03645928) Cohort 1A study assessed the combination of lifileucel, a one-time autologous TIL therapy, with pembro in patients with advanced melanoma. Eligible patients had at least one resectable lesion for TIL manufacturing and one measurable lesion for response assessment. The treatment regimen included nonmyeloablative lymphodepletion, a single lifileucel infusion, up to six doses of IL-2, and continued pembro until disease progression or unacceptable toxicity for up to 24 months. The primary endpoints were the investigator-assessed objective response rate (ORR) and the incidence of grade ≥3 treatment-emergent adverse events (TEAEs).
As of December 22, 2023, 22 patients were treated with response assessments. The median age of 48.5 years received the combination treatment. Baseline characteristics included 31.8% with liver lesions and varying stages of metastatic melanoma. The study reported a confirmed ORR of 63.6%, with 30% achieving complete response (CR) and 34.8% achieving partial response (PR). The median time to initial response was 2.5 months, with responses deepening over time. At a median follow-up of 17.2 months, the median duration of response was not reached, and 71.4% of patients had ongoing responses, including 36.4% with responses lasting over 12 months.
The safety profile was consistent with known treatments, with the most common grade ≥3 TEAEs being thrombocytopenia (68.2%), neutropenia (50.0%), and anemia (45.5%).
The combination of lifileucel and pembrolizumab demonstrated significant efficacy and durability, showing potential as a frontline treatment for advanced melanoma. These promising results support further evaluation in the phase 3 TILVANCE-301 study (NCT05727904), aiming to solidify this combination as a standard care option.
One of the questions asked at the conference was about the use of pembrolizumab as a mono therapy as an appropriate comparator arm with TIL/PD1. I listed several reasons below why it is very appropriate to consider PD1 mono therapy:
- TILVANCE 301 is comparing upfront TIL/PD1 inhibitors versus PD1 followed by immediate TIL upon confirmed progression as opposed just mono therapy alone.
- There is equipoise of dual check point inhibitor and PD1 mono therapy in the PDL1 positive group with the risk of dual checkpoint therapy outweigh a questionable benefit. In fact, Opdualag is not even approved in Europe for patients for PDL1 > 1%.
- Ipilimumab/nivolumab benefit was mainly seen only in the BRAF V600 mutated group. The wild type group seemed to not benefit as much with dual checkpoint
- Dual checkpoint therapy can be used as a salvage therapy in PD1 mono therapy progressive patients with a known response of 25-35%. As a oncology provider, I would be much more enthused to consider dual checkpoint upon progression in those who had TIL whether they received TIL/PD1 upfront or sequentially with PD1 followed by TIL.
- The long term benefit of dual checkpoint is limited to a marginal 5-10% difference. Meaning… we are still over treating the group of patients who would have done fine with PD1 mono therapy. In addition, over 50-60% of folks will still not achieve long term benefit with dual checkpoint therapy.
- Adverse effects of TIL treatment is expected, treatable, manageable, and reversible with most patients resolving the adverse effects… which are mainly due to the lymphodepletion and IL2… by day 30.
For all these reasons, patients are highly encouraged to participate in the TILVANCE 301 which is now enrolling in Europe, Australia and in North America.
Final Thoughts
The ASCO 2024 conference highlighted groundbreaking advancements in the treatment of metastatic melanoma, showcasing promising new therapies that could significantly improve patient outcomes. The triplet checkpoint therapy and the combination of TIL with pembrolizumab both offer new hope for patients and underline the importance of continued research and clinical trials.
Stay tuned for more updates from ASCO 2024 as we delve into additional exciting developments in oncology.
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. Currently practicing at the renowned Orlando Health Cancer Institute, he brings a wealth of expertise to the complex and challenging world of oncology.